Dopamine,3,4-dihydroxyphenethylamine is a neurotransmitter whose functional role appears to be intimately linked with schizophrenia. The so-called "Dopamine Hypothesis of Schizophrenia" suggested that an overactivity of the mesolimbic/mesocortical ascending dopamine systems in man was etiologic for schizophrenia. This original hypothesis has been extensively modified; although various workers have suggested that imbalances in the activity of other neurotransmitter systems such as serotonin could be involved, recent reviews have all agreed that the dopamine systems do appear in some manner to be intimately involved in schizophrenia.
However, it is not clear if an overactivity per se is involved, and it is probable that the dopamine functional changes alone are not etiologic.
A portion of the difficult lies in the difficulty of concordance in diagnosing schizophrenia, since this term seems to apply to a spectrum of disorders, ranging from affective disorder at one end to chronic paranoid psychosis at the other. Nonetheless, considerable agreement through definitions such as the DSM-IIIr and ICD has been obtained as to the symptomatology which defines the disease. Schizophrenia can be differentiated into two basic categories; that which is amenable to drug treatment, by means of conventional antipsychotic agents, and that which is not, the latter usually being spoken of as "chronic". These categories can to some degree be correlated with the relative balance of positive and negative symptomatology. The role of the negative (Bleulerian) symptomatology, although long known, has in recent years been "rediscovered".
Known neuroleptic agents, regardless of their chemical structures, are pharmacologically active upon the dopamine receptor system, as dopamine antagonists. Many of these compounds, particularly the phenothiazines, also have significant activity on other neurotransmitter systems, in particular various serotonin subtypes, particularly the 5-HT-2, muscarinic receptors, alpha-adrenoceptors, or histamine H-1 or H-2 receptors.
The clinical use of neuroleptics has provided a means for treating patients suffering from psychotic disorders. Short-term use of neuroleptics is indicated in several types of psychotic disorders, e.g., acute psychotic episodes, regardless of type; exacerbations of schizophrenia; acute manic excitement while deferring use of lithium or awaiting onset of its effects; adjunctive therapy for major depression with prominent psychotic symptoms, or when an antidepressant or ECT alone is not successful; for agitation in delirium, dementia, or severe mental retardation while seeking to identify and treat the primary basis of the problem; in certain chronic, degenerative, or idiopathic neuropsychiatric disorders with dyskinesias, such as Huntington's disease or Gilles de la Tourette's syndrome; or for ballism or hemiballism; childhood psychoses or apparently allied conditions marked by severe agitation or aggressive behavior; miscellaneous medical indications, notably nausea and vomiting, or intractable hiccups.
Additionally, continuous long-term use of neuroleptics is indicated in many psychotic disorders, such as (for more than six months) (i) primary indications such as Schizophrenia, Paranoia, Childhood psychoses, some degenerative or idiopathic neuropsychiatric disorders (notably, Huntington's disease and Gilles de la Tourette's syndrome); (ii) secondary indications such as extremely unstable manic-depressive or other episodic psychoses (unusual), otherwise unmanageable behavior symptoms in dementia, amentia, or other brain syndromes; and (iii) questionable indications such as chronic characterological disorders with schizoid, "borderline," or neurotic characteristics; substance abuse; or antisocial behavior, recurrent mood disorders. See, e.g., Baldessarini, Chemotherapy in Psychiatry, Revised and Enlarged Edition, Harvard University Press, Cambridge, Mass., (1985), the contents of which is entirely incorporated herein by reference.
Neuroleptics are also referred to as neuroplegics, psychoplegics, psycholeptics, antipsychotics and major tranquilizers, but are sometimes distinguished from non-neuroleptic anti-psychotics. Neuroleptics have recently been characterized as an agent that produces sedative or tranquilizing effects, and which also produces motor side effects, such as catalepsy or extrapyramidal symptomatology. Nonlimiting representative examples of neuroleptics include phenothiazine derivatives (e.g., chlorpromazine); thioxanthine derivatives (e.g., thiothixene); butyrophenone derivatives (e.g., haloperidol); dihydroindolone (e.g., molindone); dibenzoxazepine derivatives (e.g., loxapine); and "atypical" neuroleptics (e.g., sulpiride, remoxipiride pimozide and clozapine). See Berstein Clinical Pharmacology Littleton, Mass.: PSG Publishing (1978); Usdin et al Clinical Pharmacology in Psychiatry New York:Elsevier North-Holland (1981); and Baldessarini, supra, (1985): and, which references are herein entirely incorporated by reference.
The term "atypical neuroleptics" has been used to describe antipsychotic neuroleptics that produce few or no extrapyramidal side effects and which do not cause catalepsy in animals (See, e.g., Picket et al, Arch. Gen. Psychiatry 49:345 (May 1992). Alternatively, atypical neuroleptics, such as clozapine, have been described as those neuroleptics which have a higher affinity for D.sub.4 and D.sub.1 sites than for D.sub.2 sites (See, e.g., Davis et al Amer. J. Psych. 148:1474, 1476 (November 1991).
The long term use of all known anti-psychotics, such as neuroleptics or non-neuroleptic antipsychotics, has resulted in serious side effects, as present in Table III, such as persistent and poorly reversible motoric dysfunctions (e.g., tardive dyskinesia) in a significant number of patients.
TABLE III __________________________________________________________________________ Neurological Side Effects of Neuroleptic-Antipsychotic Drugs Period of Reaction Features maximum risk Proposed mechanism Treatment __________________________________________________________________________ Acute dystonia Spasm of muscles of 1-5 days Dopamine excess? Antiparkinsonism agents are tongue, face, neck, Acetylcholine excess? diagnostic and curative back; may mimic (i.m. or i.v., then p.o.) seizures; not hysterical Parkinsonism Bradykinesia, rigidity, 5-30 days Dopamine blockade Antiparkinsonism agents variable tremor, mask- (rarely (p.o); dopamine agonists facies, shuffling gait persists) risky? Akathisia Motor restlessness; 5-60 days Unknown Reduce dose or change drug patient may experience (commonly low doses of propranolol;.sup.a anxiety or agitation persists) antiparkinsonism agents or benzodiazepines may help Tardive Oral-facial dyskinesia; 6-24 months Dopamine excess? Prevention best; treatment dyskinesia chloreo-athetosis, some- (worse on unsatisfactory; slow spontaneous times irreversible, withdrawal) remission rarely progressive "Rabbit" Perioral tremor (late Months or Unknown Antiparkinsonism agents; reduce parkinsonism variant?); years dose of neuroleptic syndrome usually reversible Malignant Catatonia, stupor, Weeks Unknown Stop neuroleptic; antiparkinsonism fever, unstable pulse agents usually fail; syndrome and blood pressure; often helps; dantrolene bromocriptine myoglobinemia; can general supportive care crucial variable; be fatal __________________________________________________________________________ .sup.a There may be an increased risk of hypotension on interacting high doses of propranolol with some antipsychotic agents; clonidine may also b effective at doses of 0.2-0.8 mg/day, but carries a high risk of hypotension (Zubenko et al., Psychiatry Res. 11:143, 1984).
These sides effects are especially prevalent in geriatric populations, and adequate pharmacological treatment of these debilitating motoric dysfunctions is not currently available. This problem has severely limited the long-term, clinical administration of these agents.
In addition, clozapine, although apparently capable of producing less motor side effects, can cause irreversible, potentially fatal agranulocytosis in a minority of patients administered the drug. Such serious side effects limit the use of clozapine to patients who are resistant to treatment with other neuroleptics.
In the great majority of patients who do respond to the conventional neuroleptics, the clinical response, regardless of the measure used, is highly and significantly correlated with the affinity of the compounds upon D.sub.2 dopamine receptors. This correlation, which was first noted by Seeman and his colleagues in the mid-1970s, has been used as a principal supporting argument for the validity of the dopamine hypothesis of schizophrenia.
However, a minority of patients with very severe symptoms, responds poorly if at all even to elevated doses of the conventional antipsychotic agents. It has been found that clozapine, a drug recently reintroduced to clinical practice in this country after original withdrawal due to its association with a small number of cases of severe and fatal agranulocytosis, is highly effective on a majority of this subset of drug-resistant patients. Interestingly, clozapine is not potent as an antagonist for the dopamine D.sub.2 receptor, although it does have increased affinity for other dopamine receptor subtypes, such as the D.sub.4. Importantly, the drug has a mix of 5-HT-2 and D.sub.2 activity which appears to, at least in part, make it desirable as an antipsychotic. However, its potential for toxicity limits its widespread use, and makes its application to these patients expensive, as their blood CBCs must continually be monitored. Thus, the lack of a substance similar in actions to clozapine is a severe deficiency in the related art, and attempts to find such derivatives through structure-activity relationships, molecular modeling, and the like have not yielded clinically useful compounds.
A second and severe deficiency in the prior art is that all classical neuroleptic agents, as exemplified by the butyrophenones and phenothiazines, can upon long-term administration produce severe motoric symptomatology, termed tardive dyskinesia. These motor movements are uncontrollable and can range from relatively trivial manifestations to total debilitation. Tardive dyskinesia is usually poorly reversible upon discontinuation of the chronic neuroleptic, and pharmacological intervention for treatment of tardive dyskinesia itself is only moderately successful. Such motor abnormalities are known to occur in as high as 10% of the patients who are maintained on these drugs for several years; the incidence is much greater in certain groups, such as middle-aged females.
There is therefore a great need for drugs which can be termed "atypical" or "nonclassical" neuroleptics, wherein these agents will treat the symptomatology of schizophrenia either in cases which are resistant to other drugs, without toxic side effects, or whose long-term administration will not produce such toxic side effects.
One system which can be linked to the ascending mesolimbic dopamine system in a functional manner is the sigma receptor.
Sigma receptors were first postulated by Martin et al. (J. Pharmacol. Exp. Therap. 197:517-532 (1976)) to account for the behavioral effects in dogs of N-allylnormetazocine (NANM, SKF 10047)). Sigma receptors are not typical opiate receptors since the binding of sigma ligands (e.g., (.sup.3 H)-NANM) is not blocked by typical opiate receptor antagonists such as naloxone, and the enantioselectivity of NANM and other opiates for sigma sites ((+)-NANM more potent than (-)-NANM) was opposite to that seen at conventional opiate receptors. See, e.g., Walker, J. M. et al. Pharmacol. Rev. 42:355-737 (1990); Snyder, S. H. et al. J. Neuropsychiatry 1:7-15 (1989); Largent, B. L. et al. Eur. J. Pharmacol. 155:345 (1988).
It was originally thought that benzomorphans, such as NANM, bound to the same receptor site as phencyclidine (PCP), suggesting PCP receptors mediated the psychotomimetic actions of sigma ligands. See, e.g., Mendelsohn et al J. Pharmacol. Exp. Therap. 233:597-602 (1985). However, subsequent investigations showed that (.sup.3 H)-NANM) labels two sites. The first site was a PCP binding site representing a component of the receptor for the excitatory amino acid N-methyl-D-aspartate (NMDA); the second site was not labeled with (.sup.3 H)-PCP or its analogue (.sup.3 H)-TCP, but was labeled with high affinity by (.sup.3 H)-haloperidol and (+)-(.sup.3 H)-3-(+)-3-(3-hydroxyphenyl) N-(1-propyl)piperidine (+)-(.sup.3 H)-3-PPP. (Tam, S. W. (1983) "Naloxone-inaccessible sigma receptor in rat central nervous system" Proc. Natl. Acad. Sci. USA 80, 6703-6707; Largent, B. L. et al. (1986) "Pharmacological and autoradiographic discrimination of sigma and phencyclidine binding sites in the brain with (+)-SKF10047, (+)-(.sup.3 H)-3-PPP and (.sup.3 H)-1-((2-thienyl)cyclohexyl)piperidine" J. Pharmacol. Exp. Therap. 238, 739-748; Martin, W. R. (1984) "Pharmacology of opioids" Pharmacol. Rev. 35, 283-323). (.sup.3 H)-NANM binds with low affinity to the PCP site and with high affinity to the latter site, hereafter designated as the sigma-haloperidol or sigma "receptor". The two sites are readily differentiated by radioligand displacement and autoradiographic localization studies. See, e.g., Gundlach et al. Eur. J. Pharm. 113:465-466 (1985); Largent et al Neurobiol. 81:4983-4987 (1984); Gundlach et al J. Neurosci. 6:1757- 1770 (1986) McLean et al Neuroscience 25:159-269; Aaronsen et al Synapse 4:1-10 (1989). The discovery of sigma receptors, but not PCP receptors, in certain cultured cell lines is further evidence that they are separate and distinct entities. See, e.g., Yang et al Eur. J. Pharm. 164:607-610 (1989); Hellewell et al Brain Res. 527:244-253; Bowen et al Eur. J. Pharmacol. 163:309-318 (1989); Musacchio et al Life Sci 45:1721-1732 (1989).
In their exhaustive review of the literature on sigma receptors, Walker et al (Pharmacol. Rev. 42:355-737 (1990)) summarize evidence of the correlation between binding affinity to sigma sites and several functional assays, as well as endogenous ligands for sigma receptors. Su et al. Life Sci. 38:2199-2210 (1986) and Tam et al Eur. J. Pharm. 193:121.
Of potentially great importance is the finding that atypical antipsychotic drugs have moderate to high affinity for sigma receptors labeled by (.sup.3 H)-haloperidol and (+)-(.sup.3 H)-3-PPP. These include a group of piperazine (BMY 14802, BMY 13980, rimcazole, tiospirone and cinuperone), a tetrahydro-.beta.-carboline (WY 47,384) and the benzamide remoxipride. Rimcazole, remoxipride and BMY 14802 show 10 to 15-fold greater selectivity for sigma versus dopamine D2 receptors, and have little or no affinity toward PCP sites. Haloperidol itself binds with very high affinity to the sigma site. Tam et al Proc. Natl. Acad. Sci. USA 81:5618-5621 (1984).
An earlier approach to the search for new types of antipsychotics was to seek compounds which interact at dopaminergic autoreceptors, thus inhibiting the release of dopamine into the synapse rather than blocking postsynaptic receptors. (See, e.g., Carlsson, J. Neural. Transm., 47:309 (1983); Hacksell et al., J. Med. Chem., 24:1475 (1981); Johansson et al., J. Med. Chem., 28:1049 (1985); and Svensson et al., J. Neural. Transm., 65:29 (1986). The most promising compound of this type was 3-PPP, which was later found to have higher affinity for sigma receptor sites than for dopaminergic receptors. Largent et al Proc. Natl. Acad. Sci. USA 81:4983-4987 (1984).
Walker et al, supra, conclude that the establishment of a role for sigma receptors in psychosis could have profound implications for drug therapy.
The structural diversity of compounds which bind with high affinity to sigma receptor sites is very great, including butyrophenones such as haloperidol and buspirone (but not spiperone), psychotomimetic benzomorphans, and simple 3- and 4-phenylpiperidines. Walker et al., supra.
As part of a broad study of structural determinants of sigma receptor affinity, Largent et al, supra and Wikstrom et al (J. Med. Chem. 30:2169-2174 (1987)) found that a variety of analogs of 3-PPP were potent in inhibiting binding of (.sup.3 H)-3-PPP to rat brain membranes. In particular, Largent and Wikstrom found that compounds with larger N-substituents generally exhibited greater sigma affinity, suggesting lipophilicity was an important factor influencing binding to sigma receptors in this system. However, enantiospecific effects on biological activity were small. A considerable variety of substituents could be tolerated on the aromatic ring. Hydrogen bonding did not appear to be a prerequisite for binding to sigma receptors, as it is for binding to dopamine receptors. Largent and Wikstrom also assayed a series of octahydrobenzo-(f)quinolines, which are somewhat more conformationally constrained tricyclic analogues of 3-PPP. Many of these octahydrobenzo-(g)quinolines were found to be potent sigma ligands. Again, increased lipophilicity enhanced sigma potency, while compounds with methoxy substituents on the aromatic ring were more potent than hydroxy analogues. In this series of compounds, considerable stereoselectivity was now observed. Trans-fused octahydrobenzo-(f)quinolines were generally more potent than cis-fused analogues, and trans octahydrobenzo-(f)quinolines with (4aR, 10bS) stereochemistry were considerably more potent than their enantiomers (e.g., (4aS, 10bR)). In one case examined in the cis series, modest enantiospecificity (2:1) was observed. However, since trans-fused octahydrobenzo-(f)quinolines have strong agonist affinity for pre- and postsynaptic sites on D2 receptors in contrast to the weak D2 affinity of cis-fused octahydrobenzo-(f)quinolines, Largent et al (1987) suggested that the goal of finding sigma-selective ligands which are virtually devoid of D2 affinity could best be achieved with analogues of cis-fused octahydrobenzo-(f)quinolines.
Accordingly, there is a need to provide novel compounds whose stereoisomers will possess a range of effects on sigma, dopamine (D.sub.1, D.sub.2, D.sub.3, D.sub.4) and related receptor proteins, and which may modulate such receptors for use in diagnostic, therapeutic and research applications, and as alternative neuromodulating agents.